Drugs targeting APOE4 that regulate beta‐amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease

Abstract Alzheimer's disease is characterized by progressive cognitive decline, and behavioural and psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts to effectively treat the disease, only seven drugs are approved for its treatment, and only two of these prevent its progression. This highlights the need to identify new pharmacological options. This review focuses on mimetic peptides, small molecule correctors and HAE‐4 antibodies that target ApoE. These drugs reduce β‐amyloid‐induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide and furosemide show the potential to reduce the prevalence of Alzheimer's disease in humans, and antidepressants such as imipramine improve cognitive function in individuals diagnosed with Alzheimer's disease. Consistent with this, both classes of drugs have been shown to exert neuroprotective effects by inhibiting ApoE4‐catalysed Aβ aggregation in preclinical models. Moreover, peroxisome proliferator‐activated receptor ligands, particularly pioglitazone and rosiglitazone, reduce ApoE4‐induced neurodegeneration in animal models. However, they do not prevent the cognitive decline in APOE ε4 allele carriers. Finally, ApoE4 impairs the integrity of the blood–brain barrier and haemostasis. On this basis, ApoE4 modulation is a promising avenue for the treatment of late‐onset Alzheimer's disease.